Radiopharmaceutical therapy (RPT) is a highly promising alternative to chemotherapy. It is also a treatment that is orthogonal to biologic, or pathway inhibition, therapy. RPT exploits pharmaceuticals that bind to tumors to deliver radiation specifically to the targeted cells. The most promising RPT uses ?-particle emitters (?RPT). Alpha-particles cause largely irreparable DNA damage; targeting is independent of signaling pathways. The majority of ?RPT studies have focused on intracavitary administrations that confine the ?RPT to the same space as the tumor cells, studies of this type do not provide the pre-clinical data required to implement ?RPT in a wider disseminated metastasis setting. In a transgenic pre-clinical model of breast cancer metastases, we have previously demonstrated the efficacy of the ?-emitters 213Bi (T1/2=46 min) and 225Ac (T1/2=10 d; 4 ?'s per decay), conjugated to an antibody. Based on these studies and the observation that treatment did not lead to long-term cure under some circumstances, we propose to investigate ?RPT with biologic response modifiers (BRMs). Combination ?RPT-BRM studies have not been reported previously; the focus has been on combining ?RPT with cytotoxic chemotherapy. Under the hypothesis that ?RPT, is best combined with BRMs rather than agents that are directly cytotoxic and that the combination for clinical implementation is best obtained by preclinical studies supported with the modeling and dosimetry analysis that will enable extrapolation of results to human clinical trial design, we propose the following aims: 1. Identify ?RPT/BRM combinations that lead to the greatest tumor cell kill, in vitro. Ab-conjugates of the ?-particle emitters 213B, 211At or 225Ac in combination with BRMs involved in modulating: inflammation (TNF-?), protein maturation (17-AAG), gene transcription (SAHA) and DNA repair (NU7441) will be investigated, in vitro, using monolayer and spheroid cell culture conditions. 2. Assess pharmacokinetics, efficacy and toxicity of the ?RPT/BRM combinations identified in Aim 1 for further study. Evaluate tumor and normal organ distribution and pharmacokinetics at the micro (sub-organ) and macroscale (whole-organ) level. Determine the dose-limiting organ (DLO), and maximum tolerated dose (MTD) for each combination. 3. Develop a pharmarcokinetic/dosimetry model to fit response/toxicity data obtained in Aims 1 and 2. Use the model to identify the set of parameters that most impacts efficacy and toxicity. Translate pre-clinical observations into recommendations for human trial design. RPT with ?-emitters is a treatment approach that is distinct from chemotherapy and pathway inhibition therapy. It is ideally suited to the treatment of metastatic disease, a condition in which current treatment options fail. Efforts to understand and optimize ?RPT in pre-clinical models of metastatic disease will provide a substantial return on investment in terms of reducing the scope of human experimentation, especially in the context of combination therapy. Support for this proposal will enable a more effective and less toxic implementation of ?RPT against metastatases.